CN104829531A - Benazepine compound - Google Patents
Benazepine compound Download PDFInfo
- Publication number
- CN104829531A CN104829531A CN201510199726.7A CN201510199726A CN104829531A CN 104829531 A CN104829531 A CN 104829531A CN 201510199726 A CN201510199726 A CN 201510199726A CN 104829531 A CN104829531 A CN 104829531A
- Authority
- CN
- China
- Prior art keywords
- benzo
- compound
- deuterated
- chloro
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims description 64
- -1 benzazepine compound Chemical class 0.000 claims abstract description 24
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- 150000003839 salts Chemical class 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
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- GYHCTFXIZSNGJT-KLTYLHELSA-N n-[4-(7-chloro-2,2-dideuterio-5-hydroxy-4,5-dihydro-3h-1-benzazepine-1-carbonyl)-3-methylphenyl]-2-methylbenzamide Chemical compound [2H]C1([2H])CCC(O)C2=CC(Cl)=CC=C2N1C(=O)C(C(=C1)C)=CC=C1NC(=O)C1=CC=CC=C1C GYHCTFXIZSNGJT-KLTYLHELSA-N 0.000 abstract 1
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Abstract
An object of the present invention is to provide a benzazepine compound which is selected from the group consisting of: N-(4-(7-chloro-5-hydroxy-2,3,4-trihydro-5-deutero-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide, N-(4-(7-chloro-2,3-dihydro-5-hydroxy-4,4,5-trideutero-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide and N-(4-(7-chloro-5-hydroxy-2,2-dideutero-3,4,5-trihydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide.
Description
The application is the applying date is on October 25th, 2010, application number is 201080048410.3 (international application no is PCT/JP2010/068807), denomination of invention is " benzo-aza
compound " the divisional application of application.
Technical field
The present invention relates to benzo-aza
(benzazepine) compound.
Background technology
So far, have developed several compound (such as patent documentation 1 ~ 3 and non-patent literature 1 ~ 2) with vasopressin antagonistic effect (vasopressinantagonistic activity), but expected to develop the compound with more excellent vasopressin antagonistic effect.
Disclose a kind of compound with excellent vasopressin antagonistic effect in the embodiment 430 of patent documentation 3, wherein, also disclose the tolvaptan (Tolvaptan) that following formula represents.
But, in patent documentation 3, heavy-hydrogenated compound of the present invention is not disclosed completely.
Patent documentation 1: International Publication No. 2009/117144 specification sheets
Patent documentation 2: Japanese Patent Publication 7-76214 publication
Patent documentation 3: Japanese Patent No. 2905909 specification sheets
Non-patent literature 1:Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; Mori, T.; Tominaga, M.; Bioorganic & MedicinalChemistry, 1999,7 (8), 1743-1757
Non-patent literature 2:Yamamura, Y.; Nakamura, S.; Itoh, S.; Hirano, T.; Onogawa, T.; Yamashita, T.; Yamada, Y.; Tsujimae, K.; Aoyama, M.; Kotosai, K.; Ogawa, H.; Yamashita, H.; Kondo, K.; Tominaga, M.; Tsujimoto, G.; Mori, T.; Journal of Pharmacology and ExperimentalTherapeutics, 1998,287 (3), 860-867
Summary of the invention
Problem of the present invention is to provide a kind of novel benzo-aza
compound, described benzo-aza
compound has the vasopressin antagonistic effect more excellent than tolvaptan, and has other advantages, such as, formulate out the compound that metabolic stability is high, extend pharmacological validity period further.
In order to realize above-mentioned problem, the present inventor etc. conduct in-depth research repeatedly, found that by tolvaptan is carried out D body, the novel benzo-aza that following general formula (1) represents
compound has more excellent vasopressin antagonistic effect and metabolic stability.The present invention completes in view of above-mentioned knowledge.
The benzo-aza that item 1, a kind of general formula (1) represent
compound or its salt.
[in formula, R
1identical or different, represent H or D,
R
2identical or different, represent H or D,
R
3represent C1 ~ C6 alkyl, C1 ~ C6 deuteroalkyl or the full deuteroalkyl of C1 ~ C6,
R
4represent C1 ~ C6 alkyl, C1 ~ C6 deuteroalkyl or the full deuteroalkyl of C1 ~ C6,
R
5identical or different, represent H or D.]
Item 2, the benzo-aza be selected from following (1) ~ (5)
compound or its salt:
(1) N-(4-(7-chloro-5-hydroxyl-2,3,4-tri-hydrogen-5-deuterated-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide,
(2) N-(4-(chloro-2, the 3-dihydro-5-hydroxyl-4,4,5-tri-of 7-deuterated-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide,
(3) N-(4-(7-chloro-5-hydroxyl-2,2-bis-deuterated-3,4,5-tri-hydrogen-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide,
(4) N-(4-(deuterated-1H-benzo [b] azepine of the chloro-5-hydroxyl of 7--2,2,4,4,5-five
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide and
(5) N-{4-(7-chloro-5-hydroxyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl } the deuterated methyl benzamide of-3,4,5,6-tetra-deuterated-2-three.
Item 3, a kind of pharmaceutical composition, containing the benzo-aza described in item 1 or 2
compound or its salt is as effective constituent and the carrier that pharmacologically allows.
4, the benzo-aza described in item 1 or 2
compound or its salt is as the application of medicine.
Item 5, a kind of vasopressin antagonists, containing the benzo-aza described in item 1 or 2
compound or its salt is as effective constituent.
6, the pharmaceutical composition as described in item 3, described pharmaceutical composition is used for prevention or treats following disease, and described disease is selected from hypertension, edema, ascites, heart failure, renal tubal dysfunction, the abnormal syndrome (SIADH) of inappropriate secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, motion sickness (motion sickness), water metabolism obstacle, renal failure, cerebral infarction, myocardial infarction and polycystic kidney (PKD).
7, the pharmaceutical composition as described in item 3, described pharmaceutical composition is as the drug use be selected from vasodilator, depressor, water diuresis agent, anticoagulant, urea excretion accelerator, heart failure resistance agent and anti-renal failure agent.
8, a kind of method of prevention or disease therapy, described disease is selected from hypertension, edema, ascites, heart failure, renal tubal dysfunction, the abnormal syndrome (SIADH) of inappropriate secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, motion sickness, water metabolism obstacle, renal failure, cerebral infarction, myocardial infarction and polycystic kidney (PKD), described method comprise to the benzo-aza described in human or animal's item 1 or 2
compound or its salt.
The invention provides the benzo-aza that a kind of above-mentioned general formula (1) represents
compound or its salt.
As the R in general formula (1)
3and R
4c1 ~ the C6 of middle regulation, preferably C1 ~ C3 alkyl, specifically, can enumerate methyl, ethyl, n-propyl, sec.-propyl etc.
R in general formula (1)
3and R
4c1 ~ the C6 of middle regulation, preferably C1 ~ C3 deuteroalkyl, refer to that at least one hydrogen atom forming alkyl is replaced by D atom and the alkyl (wherein, not comprising the situation that whole hydrogen atoms of forming alkyl are replaced by D atom) that obtains.
Specifically, represent with following formula:
－C
nD
2n+1－mH
m
(in formula, n is the integer of 1 ~ 6, preferably 1 ~ 3, and m is the integer of 1 ~ 2n)
More specifically, deuterated methyl, two deuterated methyl, deuterated ethyl, two deuterated ethyls, three deuterated ethyls, four deuterated ethyls, deuterated propyl group, two deuterated propyl group, three deuterated propyl group, four deuterated propyl group, five deuterated propyl group etc. can be enumerated.
As the R in general formula (1)
3and R
4c1 ~ the C6 of middle regulation, the preferably full deuteroalkyl of C1 ~ C3, specifically, can enumerate complete deuterated methyl, complete deuterated ethyl, complete deuterated n-propyl, complete deuterated sec.-propyl etc.
Benzo-aza of the present invention
compound or its salt can by the method preparation recorded in following reference example and embodiment, or be such as that reference system is standby in these processes.
By the benzo-aza of the present invention that these methods obtain
compound can utilize conventional separation method to be separated in reaction system, and then purifying.As above-mentioned separation and purification process, such as, can adopt distillation method, recrystallization method, column chromatography, ion-exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, solvent extration etc.
Benzo-aza of the present invention
compound also can form preferred salt.These preferred salt can enumerate the preferred salt of the following compound (1) enumerated.
The preferred salt of compound (1) is the salt pharmacologically allowed, such as, can enumerate following salt: the metal-salts such as an alkali metal salt (such as sodium salt, sylvite etc.), alkaline earth salt (such as calcium salt, magnesium salts etc.); The inorganic base salts such as ammonium salt, alkaline carbonate (such as Quilonum Retard, salt of wormwood, sodium carbonate, cesium carbonate etc.), alkali metal hydrocarbonate (such as lithium bicarbonate, sodium bicarbonate, saleratus etc.), alkali metal hydroxide (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide etc.); Three (rudimentary) alkylamine (such as Trimethylamine, triethylamine, N-ethyl diisopropyl amine), pyridine, quinoline, piperidines, imidazoles, picoline, dimethyl aminopyridine, xylidine, N-(rudimentary) alkyl-morpholine (such as N-methylmorpholine), 1,5-diazabicyclo [4.3.0]-5-nonene (DBN), 1, organic alkali salts such as 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane (DABCO), trishydroxymethylaminomethane; The inorganic acid salts such as hydrochloride, hydrobromate, hydriodate, vitriol, nitrate, phosphoric acid salt; The organic acid salt etc. such as formate, acetate, propionic salt, oxalate, malonate, succinate, fumarate, maleate, lactic acid salt, malate, Citrate trianion, tartrate, carbonate, picrate, mesylate, esilate, tosilate, glutaminate.
In addition, at benzo-aza of the present invention
in compound, the compound of the form of addition solvate (such as hydrate, ethanolates) is also contained in benzo-aza of the present invention
in compound.As preferred solvate, hydrate can be enumerated.
Certainly the isomer such as geometrical isomer, steric isomer and optical isomer are also comprised in the compound that general formula of the present invention (1) represents.
The compound of general formula (1) and salt thereof can use with common pharmaceutical preparation form.Preparation can use conventional weighting agent, extender, tackiness agent, wetting agent, disintegrating agent, and the thinner such as tensio-active agent, lubricant or vehicle are prepared.Form as said medicine preparation can be selected from various form according to therapeutic purpose, representatively property preparation, can enumerate tablet, pill, powder, liquid preparation, suspensoid, emulsion, granule, capsule, suppository, injection (liquid preparation, suspensoid etc.) etc.
When being shaped to tablet form, as carrier, the various carriers that this area is known all the time can be widely used.As its example, such as, can use lactose, white sugar, sodium-chlor, the vehicle such as glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; The tackiness agents such as water, ethanol, propyl alcohol, simple syrup, glucose solution, starch solution, gelating soln, carboxymethyl cellulose, shellac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone; The disintegrating agents such as dry starch, sodium alginate, agar powder, laminarin powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester class, sodium lauryl sulphate, glyceryl monostearate, starch, lactose; White sugar, tristearin, theobroma oil powder, hydrogenation wet goods disintegration inhibitor; The absorption enhancer such as quaternary ammonium hydroxide, sodium lauryl sulphate; The wetting Agent for Printing Inks such as glycerine, starch; The sorbent materials such as starch, lactose, kaolin, wilkinite, colloidal magnesium; The lubricants etc. such as Talc, stearate, boric acid powder, polyoxyethylene glycol.And then, tablet can make as required employ common coating material tablet, such as coated tablet, gel pack garment piece, ECT, thin membrane coated tablet or double-layer tablets, multilayer tablet etc.
When being shaped to pill form, as carrier, current known carrier in this area can be widely used.As its example, such as, can use the vehicle such as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, kaolin, talcum; The tackiness agents such as gum arabic powder, tragacanth gum powder, gelatin, ethanol; The disintegrating agent such as laminarin, agar etc.
When being shaped to suppository form, as carrier, current known carrier can be widely used.As its example, such as, can enumerate the ester class, gelatin, semi-synthetic glyceryl ester etc. of polyoxyethylene glycol, theobroma oil, higher alcohols, higher alcohols.
Capsule can be prepared as follows, that is, mixed with the above-mentioned various carriers enumerated by effective constituent compound according to conventional methods, be filled in hard gelatine capsule, soft capsule etc.
When preparing injection, preferred liquid preparation, emulsion and suspensoid are by sterilizing, and it is isotonic with blood, when being shaped to above-mentioned form, as thinner, whole thinners conventional in this area can be used, such as, can use water, ethanol, polyoxyethylene glycol, propylene glycol, ethoxylated isostearyl alcohols, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester class etc.
It should be noted that, in these cases, in order to prepare isotonicity solution, the salt of substantial amount, glucose or glycerine can be contained in pharmaceutical preparation, in addition, common solubilizing agent, buffer reagent, analgesic agent etc. can also be added.Tinting material, sanitas, spices, sweeting agent etc. and other drug can also be contained further as required in pharmaceutical preparation.
For the amount of the compound or its salt of the general formula that should contain in pharmaceutical preparation of the present invention (1), be not particularly limited, suitably can select in wider scope, but usually in preparation compositions containing having an appointment 0.1 % by weight ~ 70 % by weight, preferably 0.1 % by weight ~ 30 % by weight.
The method of administering same of pharmaceutical preparation of the present invention is not particularly limited, can adopt the method adapted with the degree etc. of the conditions such as various dosage form, patient age, sex, disease carry out to.Such as, when being tablet, pill, liquid preparation, suspensoid, emulsion, granule and capsule, carry out oral give with.In addition, during for injection, carry out separately intravenously to or with the common fluid infusion such as glucose or amino acid be mixed in row vein to, and then, can carry out separately as required intramuscular, intracutaneous, subcutaneous or intraperitoneal to.During for suppository, carry out internal rectum give with.
Giving and amount of pharmaceutical preparation of the present invention, suitably can select according to the degree of the conditions such as usage, patient age, sex, disease etc., the amount of usual effective constituent be every day every 1kg body weight to about about 0.1 ~ 10mg.In addition, preferably give with the preparation of unit form in contain effective constituent compound with the scope of about 1 ~ 200mg.
Benzo-aza of the present invention
compound has excellent vasopressin antagonistic effect.It is such as vasorelaxation action that vasopressin antagonistic effect acts on more specifically, the effect of reducing blood pressure, hepatic glucose release restraining effect, proliferation of glomerular mesangial cells restraining effect, water diuresis effect, platelet aggregation restraining effect, vomiting restraining effect, urea excretion promoter action, VIII cytokine secretion restraining effect, the hyperfunction effect of heart function, mesangial cell shrinks restraining effect, the newborn restraining effect of hepatic glucose, Aldosterone Secretion restraining effect, endothelium peptide produces restraining effect, renin secretion regulating effect, regulation of memory, thermoregulation effect, prostaglandin(PG) produces regulating effect etc.Therefore, of the present invention containing benzo-aza
compound as the pharmaceutical composition of effective constituent such as vasodilator, depressor, water diuresis agent, anticoagulant, urea excretion accelerator, heart failure resistance agent, anti-renal failure agent etc. are useful, to hypertension, edema, ascites, in heart failure, renal tubal dysfunction, the abnormal syndrome (SIADH) of inappropriate secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, motion sickness, water metabolism obstacle, renal failure, cerebral infarction, myocardial infarction, polycystic kidney (PKD), and the prevention of various ischemic diseases etc. or treatment are effectively.
Benzo-aza of the present invention
the feature of compound is, the time length of few side effects, drug effect is long.
Embodiment
Below provide reference example and embodiment, illustrate the present invention further.
Reference example 1
N-(4-(7-chloro-5-oxygen base-2,3,4-tri-hydrogen-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl) preparation of-2-methyl benzamide
To N-(4-(7-chloro-5-hydroxyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide (2g) methylene dichloride (40mL) suspension in add Manganse Dioxide (2g), reflux 7 hours.After reaction mixture is cooled, with diatomite filtration, after washed with dichloromethane, utilize silica gel column chromatography (normal hexane: ethyl acetate=10:1 → 3:1) to carry out purifying, obtain 0.94g title compound.Proterties: colorless amorphous powder
1H－NMR(CDCl
3)δppm
1.91－1.31(2H,m),2.43(3H,s),2.49(3H,s),2.89(2H,t,J＝6.3Hz),3.30－4.60(2H,m),6.48－7.00(2H,m),7.01－7.70(8H,m),7.78(1H,s).
Embodiment 1
N-(4-(7-chloro-5-hydroxyl-2,3,4-tri-hydrogen-5-deuterated-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl) preparation of-2-methyl benzamide
In 0 DEG C, to N-(4-(7-chloro-5-oxygen base-2,3,4-tri-hydrogen-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide (0.4g) deuterated methanol (10mL) solution in add boron deuterate sodium (Sodium borodeuteride) (0.045g), at the same temperature stir 2 hours.In gained reaction mixture, add heavy water (2mL), stir after 10 minutes, add water, be extracted with ethyl acetate.Gained water layer is extracted with ethyl acetate again.Merge gained ethyl acetate layer, used anhydrous magnesium sulfate drying, then, distillation, except desolventizing, by residue recrystallization from acetone-diethyl ether, obtains the title compound of 0.35g.
Yield: 87%
Proterties: white powder
1H－NMR(DMSO－d6,80℃)δppm
1.40－2.19(4H,m),2.36(3H,s),2.38(3H,s),3.35－4.94(2H,br),5.35(1H,s),6.56－7.70(10H,m),9.93(1H,brs)
MS:(M
+,449)
Fusing point: 227.8 DEG C.
Embodiment 2
N-(4-(chloro-2, the 3-dihydro-5-hydroxyl-4,4,5-tri-of 7-deuterated-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl) preparation of-2-methyl benzamide
To N-(4-(7-chloro-5-oxygen base-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide (300mg) deuterated methanol (10mL) solution in add 0.05M sodium hydroxide deuterated methanol solution (13 μ l), stir in argon atmospher, under room temperature.Stir after 16 hours, utilize
1h-NMR confirms that 4 protons disappear, and at 0 DEG C, adds boron deuterate sodium (0.037g) in reaction solution, stirs 2 hours at the same temperature.In gained reaction mixture, add heavy water (2mL), stir after 10 minutes, add water, be extracted with ethyl acetate.Gained water layer is extracted with ethyl acetate again.Merge gained ethyl acetate layer, by it with after anhydrous magnesium sulfate drying, distillation, except desolventizing, by residue recrystallization from acetone-diethyl ether, obtains the title compound of 0.22g.
Yield: 73%
Proterties: white powder
1H－NMR(DMSO－d6,80℃)δppm
1.51－2.06(2H,m),2.36(3H,s),2.38(3H,s),3.36－5.02(2H,br),5.34(1H,s),6.58－7.70(10H,m),9.94(1H,brs)
MS:(M
+,451)
Fusing point: 225.1 DEG C.
Reference example 2
The preparation of 4-(the chloro-2-nitrophenyl of 5-)-4-(trimethylsiloxy) butyric acid ethyl ester
Under reduced pressure, by zinc bromide (1.21g) heat drying after 15 minutes, add the chloro-2-nitrobenzaldehyde (5.0g) of 5-and methylene dichloride (70mL) wherein.At 0 DEG C, instill [(1-oxyethyl group cyclopropyl) oxo] trimethyl silane (6.50mL) in gained mixture after, at room temperature stir 6 hours.After reaction solution concentrating under reduced pressure, by residue alkaline silica gel column chromatography (normal hexane: ethyl acetate=20:1 → 10:1) purifying, obtain the title compound of 4.76g.
Yield: 49%
Proterties: yellow oil
1H－NMR(CDCl
3)δppm
0.05(9H,s),1.26(3H,t,J＝7.1Hz),1.80－2.00(1H,m),2.01－2.20(1H,m),2.45(2H,t,J＝7.5Hz),4.13(2H,q,J＝7.1Hz),5.29－5.45(1H,m),7.37(1H,dd,J＝2.4Hz,8.7Hz),7.80(1H,d,J＝2.4Hz),7.91(1H,d,J＝8.7Hz).
Reference example 3
The preparation of 4-(the chloro-2-nitrophenyl of 5-)-4 hydroxybutyric acid ethyl ester
In ethanol (25mL)-water (5mL) solution of 4-(the chloro-2-nitrophenyl of 5-)-4-(trimethylsiloxy) butyric acid ethyl ester (4.76g), add Citric Acid (0.51g), at room temperature stir 1.5 hours.Water is added in reaction solution, be extracted with ethyl acetate, ethyl acetate layer is used saturated common salt water washing, then anhydrous magnesium sulfate drying is used, then distillation is except desolventizing, by residue silica gel column chromatography (normal hexane: ethyl acetate=20:1 → 10:1) purifying, obtain the title compound of 3.8g.
Proterties: pale yellow oil
1H－NMR(CDCl
3)δppm
1.29(3H,t,J＝7.1Hz),1.91－2.09(1H,m),2.10－2.25(1H,m),2.51－2.72(2H,m),3.50(1H,d,J＝3.9Hz),4.18(2H,q,J＝7.1Hz),5.31－5.43(1H,m),7.39(1H,dd,J＝2.3Hz,8.7Hz),7.90(1H,d,J＝2.3Hz),7.95(1H,d,J＝8.7Hz).
Reference example 4
The preparation of 4-(t-butyldimethylsilyloxy)-4-(the chloro-2-nitrophenyl of 5-) butyric acid ethyl ester
In anhydrous dimethyl formamide (25mL) solution of 4-(the chloro-2-nitrophenyl of 5-)-4 hydroxybutyric acid ethyl ester (3.8g), add imidazoles (5.4g) and TERT-BUTYL DIMETHYL CHLORO SILANE (3.98g), at room temperature stir 16 hours.Water is added in reaction solution, be extracted with ethyl acetate, ethyl acetate washed with water is washed three times, then anhydrous magnesium sulfate drying is used, then distillation is except desolventizing, by residue alkaline silica gel column chromatography (normal hexane: ethyl acetate=20:1 → 10:1) purifying, obtain 5.3g title compound with quantitative yield.
Proterties: yellow oil
1H－NMR(DMSO－d6)δppm
－0.19(3H,s),0.03(3H,s),0.84(9H,s),1.17(3H,t,J＝7.1Hz),1.81－2.11(3H,m),2.33－2.45(1H,m),4.02(2H,q,J＝7.1Hz),5.17－5.29(1H,m),7.64(1H,dd,J＝2.4Hz,8.7Hz),7.74(1H,d,J＝2.4Hz),8.01(1H,d,J＝8.7Hz).
Reference example 5
Chloro-3,4,5-tri-hydrogen-1H-benzo [b] azepines of 5-(t-butyldimethylsilyloxy)-7-
the preparation of-2 (3H)-one
Tetrahydrofuran (THF) to 4-(t-butyldimethylsilyloxy)-4-(the chloro-2-nitrophenyl of 5-) butyric acid ethyl ester (4.6g): add 5M-aqueous sodium hydroxide solution (3.43mL in ethanol (1:1) (40mL) solution, 17.2mmol), stir 1 hour at 30 DEG C.In reaction mixture, add 10% aqueous solution of citric acid, be extracted with ethyl acetate.Ethyl acetate layer is used saturated common salt water washing, then, after anhydrous magnesium sulfate drying, distillation is except desolventizing.In residue, add ethyl acetate (40mL), after adding platinum oxide (0.26g) under nitrogen atmosphere, stir 3 hours under 1 atmosphere of hydrogen.Platinum oxide is carried out diatomite filtration, washs by ethyl acetate.Filtrate is concentrated, in dry DMF (60mL) solution, add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.63g), I-hydroxybenzotriazole hydrate (2.1g), triethylamine (1.91mL), at room temperature stir 3 days.In reaction mixture, add water, be extracted with ethyl acetate, gained water layer is extracted with ethyl acetate again.Merge gained ethyl acetate layer, washed with water three times, after anhydrous magnesium sulfate drying, distillation is except desolventizing.By residue alkaline silica gel column chromatography (normal hexane: ethyl acetate=20:1 → 8:1) purifying, obtain the title compound of 0.55g.
Yield: 15%
Proterties: colorless amorphous powder
1H－NMR(CDCl
3)δppm
0.01(3H,s),0.08(3H,s),0.93(9H,s),1.89－2.06(2H,m),2.20－2.36(2H,m),2.43－2.67(1H,m),4.96(1H,dd,J＝7.1Hz,10.1Hz),6.87(1H,d,J＝8.4Hz),7.16(1H,brs),7.23(1H,dd,J＝2.1Hz,8.4Hz),7.58(1H,d,J＝2.1Hz).
Reference example 6
Chloro-2,2-bis-deuterated-3,4,5-tri-hydrogen-1H-benzo [b] azepines of 5-(t-butyldimethylsilyloxy)-7-
preparation
At 0 DEG C, to chloro-3,4,5-tri-hydrogen-1H-benzo [b] azepines of 5-(t-butyldimethylsilyloxy)-7-
add boron deuterate sodium (424mg) in anhydrous THF (30mL) solution of-2 (3H)-one (550mg), instill boron trifluoride ethyl ether complex (0.855mL) at the same temperature.At 0 DEG C, stir gained mixture after 1 hour, add boron deuterate sodium (210mg).At room temperature stir after 2 hours, at 0 DEG C, instill heavy water (4mL), stir 15 minutes at the same temperature.Then in reaction mixture, add ethanol (10mL), at room temperature stir 20 minutes.In reaction mixture, add water, be extracted with ethyl acetate, gained water layer is extracted with ethyl acetate again.Merge gained ethyl acetate layer, by it with after anhydrous magnesium sulfate drying, distillation is except desolventizing.By residue alkaline silica gel column chromatography (normal hexane: ethyl acetate=20:1 → 10:1) purifying, the title compound of 470mg.
Proterties: colorless amorphous powder
1H－NMR(CDCl
3)δppm
0.07(3H,s),0.09(3H,s),0.95(9H,s),1.70－1.90(2H,m),1.94－2.12(1H,m),3.58－3.80(1H,m),4.61－4.79(1H,m),6.63(1H,d,J＝8.3Hz),7.00(1H,dd,J＝2.5Hz,8.3Hz),7.48(1H,dd,J＝0.9Hz,2.5Hz).
Embodiment 3
N-(4-(7-chloro-5-hydroxyl-2,2-bis-deuterated-3,4,5-tri-hydrogen-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl) preparation of-2-methyl benzamide
In methylene dichloride (30mL) suspension of 2-methyl-4-(2-methyl benzamide) phenylformic acid (450mg), add thionyl chloride (0.14mL) and dimethyl formamide (1.2 μ l), reflux 3 hours.After reaction solution concentrating under reduced pressure, use methylbenzene azeotropic secondary.
At 0 DEG C, to chloro-2,2-bis-deuterated-3,4,5-tri-hydrogen-1H-benzo [b] azepines of 5-(t-butyldimethylsilyloxy)-7-
(500mg) instill triethylamine (0.24mL) in methylene dichloride (50mL) solution, then instill methylene dichloride (5mL) solution of the acyl chlorides of above-mentioned preparation.Stir after 4 hours at the same temperature, in reaction solution, add water, use dichloromethane extraction.Dichloromethane layer is used saturated common salt water washing, after anhydrous magnesium sulfate drying, distillation is except desolventizing, by residue alkaline silica gel column chromatography (normal hexane: ethyl acetate=10:1 → 3:1) purifying, obtain N-(4-(5-(the t-butyldimethylsilyloxy)-7-chloro-2 of 570mg, 2-bis-deuterated-3,4,5-tri-hydrogen-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide, and then, at 0 DEG C, in this THF (40mL) solution, add the THF solution (1.51mL) of 1N-tetrabutyl ammonium fluoride.After gained mixture is at room temperature stirred 30 minutes, at 0 DEG C, add 1M-HCl, be extracted with ethyl acetate.Washed by ethyl acetate washed with water, after anhydrous magnesium sulfate drying, distillation is except desolventizing.By residue recrystallization from acetone-diethyl ether, obtain the title compound of 370mg.
Proterties: white powder
1H－NMR(DMSO－d6,80℃)δppm
1.41－2.06(2H,m),2.36(3H,s),2.38(3H,s),4.78－4.96(1H,m),5.37(1H,d,J＝4.3Hz),6.61－7.69(10H,m),9.94(1H,brs)
MS:(M
+,450)
Fusing point: 223.7 DEG C.
Embodiment 4
N-(4-(deuterated-3,4-dihydro-1H-benzo [b] azepines of 7-chloro-5-oxygen base-2,2-bis-
-1-carbonyl)-3-aminomethyl phenyl) preparation of-2-methyl benzamide
To N-(4-(7-chloro-5-hydroxyl-2,2-bis-deuterated-3,4,5-tri-hydrogen-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide (0.25g) methylene dichloride (50mL) suspension in add Manganse Dioxide (482mg), reflux 8 hours.After being cooled by reaction mixture, use diatomite filtration.By filtrate washed with dichloromethane, residue silica gel column chromatography (normal hexane: the ethyl acetate=10:1 → 3:1) purifying after filtrate being concentrated, obtains the title compound of 0.24.
Proterties: colorless amorphous powder
1H－NMR(CD
3OD,50℃)δppm
1.98－2.18(2H,m),2.38(3H,s),2.41(3H,s),2.73－2.91(2H,m),6.73－7.78(10H,m).
N-(4-(deuterated-1H-benzo [b] azepine of the chloro-5-hydroxyl of 7--2,2,4,4,5-five
-1-carbonyl)-3-aminomethyl phenyl) preparation of-2-methyl benzamide
To N-(4-(deuterated-3,4-dihydro-1H-benzo [b] azepines of 7-chloro-5-oxygen base-2,2-bis-
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide (250mg) deuterated methanol (10mL) solution in add 0.05M-sodium hydroxide deuterated methanol solution (11 μ L), in argon atmospher, in stirred at ambient temperature.Stir after 18 hours, utilize
1h-NMR confirms 4 protons and disappears.Form deuterated methanol (10mL) suspension after reaction solution is concentrated, at 0 DEG C, add boron deuterate sodium (0.030g), stir 2 hours at the same temperature.In gained reaction mixture, add heavy water (2mL), stir after 20 minutes, add water, be extracted with ethyl acetate.Gained water layer is extracted with ethyl acetate again.Merge gained ethyl acetate layer, by it with after anhydrous magnesium sulfate drying, distillation, except desolventizing, by residue recrystallization from acetone-diethyl ether, obtains the title compound of 0.17g.
Proterties: white powder
1H－NMR(DMSO－d6,80℃)δppm
1.60－2.00(2H,m),2.36(3H,m),2.38(3H,s),5.34(1H,s),6.51－7.70(10H,m),9.93(1H,brs)
MS:(M
+,453)
Fusing point: 224.7 DEG C.
It should be noted that, utilize
1it is N-(4-(deuterated-3-hydrogen-1H-benzo [b] azepine of 7-chloro-5-oxygen base-2,2,4,4-tetra-that H-NMR confirms the compound generated when 4 protons disappear
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide, its NMR composes as follows.
1H－NMR(CD
3OD,50℃)δppm
1.94－2.19(2H,m),2.38(3H,s),2.41(3H,s),6.76－7.78(10H,m).
Reference example 7
N-{4-(7-chloro-5-oxygen base-2,3,4-tri-hydrogen-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl } preparation of the deuterated methyl benzamide of-3,4,5,6-tetra-deuterated-2-three
To chloro-2,3,4-tri-hydrogen-1H-benzo [b] azepines of 1-(4-amino-2-methyl benzoyl)-7-
-5 (2H)-one (2.39g), 3,4,5, the deuterated tolyl acid of the deuterated-2-of 6-tetra-three (1.04g) and triethylamine (1.4mL, 2-(7-azepine-1H-benzotriazole-1-base)-1,1,3 is added in dimethyl formamide (24mL) solution 10mmol), 3-tetramethyl-urea hexafluorophosphate (3.04g), stirs 4 hours under nitrogen atmosphere, in 65 DEG C.After reaction solution is concentrated, add 0.1N hydrochloric acid (100mL), extract by ethyl acetate (100mL).Washed with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt successively by organic layer, with anhydrous sodium sulfate drying, then distillation is except desolventizing.By residue obtained silica gel medium pressure column chromatography (methylene dichloride → dichloromethane/ethyl acetate=3/1) purifying, obtain the title compound (3.1g) of tawny amorphous solid.
Proterties: tawny amorphous powder
1H‐NMR(300MHz,CDCl
3)δppm
1.86‐2.31(2H,m),2.40(3H,s),2.87(2H,t,J＝6.3Hz),3.16‐5.04(2H,br),6.42‐7.41(4H,m),7.45‐7.70(2H,m),7.76(1H,br.s).
Embodiment 5
N-{4-(7-chloro-5-hydroxyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl } preparation of the deuterated methyl benzamide of-3,4,5,6-tetra-deuterated-2-three
At 0 DEG C, to N-{4-(7-chloro-5-oxygen base-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl }-3,4, add sodium borohydride (300mg) in methyl alcohol (30mL) suspension of the deuterated methyl benzamide of the deuterated-2-of 5,6-tetra-three (3.0g), at room temperature stir 30 minutes afterwards.In reaction solution, add 1N hydrochloric acid (40mL) and water (100mL), extract by ethyl acetate (150mL).Organic layer is used successively saturated sodium bicarbonate aqueous solution, saturated common salt water washing, with anhydrous sodium sulfate drying, then distillation is except desolventizing.By residue obtained silica gel medium pressure column chromatography (dichloromethane/ethyl acetate=3/1 → 1/1) purifying, then by residue recrystallization from aqueous methanol, obtain the title compound (2.36g) into white powder.
Proterties: white powder
Fusing point: 225 ?228 DEG C (second alcohol ?water).
Pharmacological testing 1
Test method and data analysis method
People V1a expression of receptor HeLa cell (V1a-HeLa) cultivated in 12 orifice plates or people V2 expression of receptor HeLa cell (V2-HeLa) cultivated in 24 orifice plates are washed 2 times with D-PBS.
[
3h] AVP in conjunction with in saturation experiments, AVP (1 μM) exist under and not in the presence of, add in hole in reaction solution (DMEM-0.3%BSA) various concentration [
3h] AVP (V1a-HeLa; 0.4nM ~ 7nM, V2-HeLa; 0.3nM ~ 6nM) make it react.On the other hand, [
3h] AVP in conjunction with in Inhibition test, at each compound (V1a-HeLa of various concentration; 1nM ~ 100nM, V2-HeLa; 0.1nM ~ 10nM) existence under, in reaction solution in hole add [
3h] AVP (V1a-HeLa; 3.3nM ~ 3.7nM, V2-HeLa; 1.4nM ~ 1.7nM) make it react.
At 4 DEG C, make after 2 hours, to wash 2 time with D-PBS with the substance reaction in upper plate, with containing 0.1%SDS 0.1N NaOH reclaim cell, utilize liquid flashing counter measuring [
3h] radioactivity of AV.More than measure and carry out secondary.
Dissociation constant (K
d) and acceptor number (B
max) by utilize Scatchard plot resolve [
3h] AVP calculates in conjunction with the result of saturation experiments.[
3h] AVP in conjunction with in Inhibition test, compound exist under [
3h] combination rate of AVP calculates according to the following formula.
Combination rate (%)=(B-NSB)/(TB-NSB) × 100
(B: under each compound exists [
3h] binding capacity of AVP, NSB: under existing at non-marked AVP1 μM [
3h] binding capacity of AVP, TB: non-marked AVP 1 μM not in the presence of [
3h] binding capacity of AVP)
Utilize above-mentioned combination rate, calculate suppression 50% [
3h] concentration (IC of each compound that combines of AVP
50), use gained IC
50, according to following formula, calculate the suppression constant (K of each compound
i).
K
i＝IC
50/(1+[L]/K
d)
(K
d: [
3h] dissociation constant of AVP, [L]: use in test [
3h] concentration of AVP)
As a result, confirm that there is excellent vasopressin antagonistic effect.
Pharmacological testing 2
Metabolic stability is tested
reaction system and cultivation
With reference to the method (reference 1,2) of the people such as Obach and Jones, be prepared by following reaction system, metabolic stability is evaluated.It should be noted that, people's hepatomicrosome is purchased from BD Gentest and use.Assessing compound is prepared as follows and is used, that is, be dissolved in DMSO by assessing compound, makes its concentration be 10mM, then uses dilution in acetonitrile, be prepared as 100 μMs.
< reaction system >
Number of cases: n=4
< reaction conditions >
By reaction system preculture 5 minutes at 37 DEG C of not adding coenzyme, then add coenzyme and start reaction.After adding coenzyme, cultivate 0,5,10,20,30 and 60 minute, take out a part of reaction solution every the specified time, the reaction solution of taking-up is added in the acetonitrile solution containing internal standard substance matter, reaction is stopped.
analytical procedure
Reaction carries out centrifugation after stopping, by unchanged material residual in assaying reaction system in supernatant injection liquid chromatography tandem mass spectrum (LC-MS/MS).Ionization carries out electron spray ionisation (ESI) according to cation detection pattern, utilizes the selective reaction using parent ion and the daughter ion set to detect (MRM) method.
data parsing
The residual rate of assessing compound calculates according to following formula.
Residual rate=(peak area of the peak area/internal standard substance matter of assessing compound during reaction times t minute) ÷ (peak area of the peak area/internal standard substance matter of assessing compound during 0 minute reaction times)
Nonlinear least square method parsing is carried out to residual rate and incubation time, obtains disappearance velocity constant (0.693/t
1/2), and then, utilize formula (1) to obtain CLint (Clint).
Clint(μL/min/mg)＝(0.693/t
1/2)÷0.2(mg/mL)×1000 (1)
For the CLint of each assessing compound of gained, Dunnett two-tailed test is utilized to compare between the significant difference group relative to tolvaptan.
achievement
To tolvaptan and heavy hydrogen substituent (embodiment 4) thereof, the metabolic stability of appraiser's liver microsomes.CLint (Clint) as the index of metabolic stability is respectively:
Tolvaptan: 214 ± 4.3 (μ L/min/mg)
Embodiment 4:166 ± 5.3* (μ L/min/mg)
(two－tailed Dunnett’s test,*:p<0.001)
The compound of embodiment 4 significantly improves metabolic stability compared with tolvaptan.
reference
1.R.S.Obach.Drug Metab.Dispos.1999(27):1,350－1,359
2.H.Jones and J.B.Houston,Drug Metab Dispos,2004(32):973－982
Claims (5)
1. be selected from the benzo-aza in following (1) ~ (3)
compound or its salt,
(1) N-(4-(7-chloro-5-hydroxyl-2,3,4-tri-hydrogen-5-deuterated-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide,
(2) N-(4-(chloro-2, the 3-dihydro-5-hydroxyl-4,4,5-tri-of 7-deuterated-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide and
(3) N-(4-(7-chloro-5-hydroxyl-2,2-bis-deuterated-3,4,5-tri-hydrogen-1H-benzo [b] azepine
-1-carbonyl)-3-aminomethyl phenyl)-2-methyl benzamide.
2. a pharmaceutical composition, containing benzo-aza according to claim 1
compound or its salt is as effective constituent and the carrier that pharmacologically allows.
3. a vasopressin antagonists, containing benzo-aza according to claim 1
compound or its salt is as effective constituent.
4. pharmaceutical composition as claimed in claim 2, described pharmaceutical composition is used for prevention or treats following disease, and described disease is for being selected from the disease in hypertension, edema, ascites, heart failure, renal tubal dysfunction, the abnormal syndrome (SIADH) of inappropriate secretion, liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, motion sickness, water metabolism obstacle, renal failure, cerebral infarction, myocardial infarction and polycystic kidney (PKD).
5. pharmaceutical composition as claimed in claim 2, described pharmaceutical composition is as the drug use be selected from vasodilator, depressor, water diuresis agent, anticoagulant, urea excretion accelerator, heart failure resistance agent and anti-renal failure agent.
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| JP2009245434 | 2009-10-26 | ||
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| HU231206B1 (en) | 2017-12-15 | 2021-10-28 | Richter Gedeon Nyrt. | Triazolobenzazepines |
| TW201938171A (en) | 2017-12-15 | 2019-10-01 | 匈牙利商羅特格登公司 | Tricyclic compounds as vasopressin V1a receptor antagonists |
| JP6868089B2 (en) * | 2018-12-28 | 2021-05-12 | 大塚製薬株式会社 | Medicine |
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| US5753677A (en) * | 1989-10-20 | 1998-05-19 | Otsuka Pharmaceutical Co., Ltd. | Benzoheterocyclic compounds |
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| WO2009117144A1 (en) * | 2008-03-20 | 2009-09-24 | Concert Pharmaceuticals, Inc. | Benzazepine compounds |
| CN101687788A (en) * | 2006-10-19 | 2010-03-31 | 奥斯拜客斯制药有限公司 | The indoles that replaces |
Family Cites Families (6)
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| HK1003107A1 (en) | 1989-10-20 | 1998-10-09 | Otsuka Pharmaceutical Co., Ltd. | Benzoheterocyclic compounds |
| JP2905909B2 (en) * | 1991-04-19 | 1999-06-14 | 大塚製薬株式会社 | Vasopressin antagonist |
| US5258510A (en) * | 1989-10-20 | 1993-11-02 | Otsuka Pharma Co Ltd | Benzoheterocyclic compounds |
| AU683483B2 (en) * | 1993-07-21 | 1997-11-13 | Astellas Pharma Inc. | Fused benzazepine derivative and pharmaceutical composition containing the same |
| CA2616383C (en) * | 2005-07-29 | 2015-06-09 | Concert Pharmaceuticals Inc. | Novel benzo[d][1,3]-dioxol derivatives |
| TWI459947B (en) * | 2007-06-26 | 2014-11-11 | Otsuka Pharma Co Ltd | Benzodiazepine compounds and pharmaceutical preparations |
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2010
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| US20130131045A1 (en) | 2013-05-23 |
| EA022253B1 (en) | 2015-11-30 |
| CA2778756A1 (en) | 2011-05-05 |
| ZA201202640B (en) | 2013-06-26 |
| CN104447555A (en) | 2015-03-25 |
| CN102753530A (en) | 2012-10-24 |
| PH12012500762A1 (en) | 2012-11-26 |
| BR112012009784A2 (en) | 2016-05-17 |
| IL219132A0 (en) | 2012-06-28 |
| KR20120092139A (en) | 2012-08-20 |
| AU2010312651A1 (en) | 2012-05-03 |
| CO6481003A2 (en) | 2012-07-16 |
| EP2495236A1 (en) | 2012-09-05 |
| EP2495236A4 (en) | 2013-03-27 |
| EA201290228A1 (en) | 2012-12-28 |
| JPWO2011052519A1 (en) | 2013-03-21 |
| US8940727B2 (en) | 2015-01-27 |
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